Is ERBB2 p.Pro523= (c.1569A>G) pathogenic?

ERBB2 p.Pro523= (c.1569A>G) is classified Benign in ERBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Rare (popmax 0.341%, nfe).

How common is ERBB2 p.Pro523= (c.1569A>G) in the general population?

ERBB2 p.Pro523= (c.1569A>G) is rare (popmax 0.341%, nfe) (gnomAD).

ERBB2 p.Pro523=

c.1569A>G · rs55928971 · VCV723566

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.341%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -5.3
Overall
CADD	0.625	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.341% European (non-Finnish) · 4,018/1,177,912 alleles

Filtering AF 0.332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.308% 4,955/1,609,156 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.979%	102
European (non-Finnish)grpmax	0.341%	293
Remaining individualsnot grpmax-eligible	0.273%	366
Admixed American	0.0862%	1,160
African / African-American	0.0547%	1,827
South Asian	0.0431%	2,318
Middle Eastern	0.0344%	2,908
Ashkenazi Jewishnot grpmax-eligible	0.0341%	2,936

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ERBB2
Protein: p.Pro523=
Coding: c.1569A>G
MANE Select: NM_004448
dbSNP: rs55928971
Type: single nucleotide variant
Location: chr17:39716356 (GRCh38)
Gene constraint: LOEUF 0.518 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 74.65 · 63 PDB
Residue 523: a β-strand; a disulfide bond

Full ERBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERBB2 p.Pro523Ser Uncertain significance ★ ⚠ same residue
ERBB2 p.Ala598Asp Uncertain significance ★★ ⚠ same type
ERBB2 p.Ala644Thr Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg1048Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188Cys Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg188His Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg190Gln Uncertain significance ★★ ⚠ same type
ERBB2 p.Arg203His Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/erbb2-p-pro523 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown